Allan-Herndon-Dudley Syndrome | Triac Trial in MCT8 Patients
Allan-Herndon-Dudley Syndrome research study
What is the primary objective of this study?
This therapeutical trial will be conducted in patients with the Allan-Herndon-Dudley Syndrome (AHDS), which is mutations in MCT8. MCT8 is a thyroid hormone (TH) transporter which is crucial for the transport of TH from the blood into different tissues. Dysfunction of MCT8 results in a lack of TH (hypothyroidism) in tissues that depend on MCT8 for TH uptake. This local hypothyroidism in the brain of these patients causes severe psychomotor retardation. In addition, TH serum parameters are highly abnormal in AHDS: high T3, low T4 and normal TSH levels. The high serum T3 levels cause local hyperthyroidism in tissues that do not depend on MCT8 for cellular transport of TH, resulting in a low body weight and reduced muscle mass. Currently, no adequate treatment is available for the AHDS. A T3 analog that does not depend on MCT8 for its cellular entry could, at least partially, restore the abnormalities found in AHDS. Several in vivo, in vitro and animal studies have shown that the T3 analog Triac is a very promising candidate: 1. Triac binds to the same TH receptors as T3; 2. Cellular uptake of Triac does not depend on functional MCT8. Hence, in AHDS patients Triac will also be available in tissues that require functional MCT8 for TH uptake, e.g. the brain; 3. In vitro studies have shown that neuronal cells differentiate equally well in the presence of either Triac or T3; 4. In Mct8 deficient mice, Triac is taken up by the brain and suppresses serum TSH levels; consequently, serum T3 and T4 levels were lowered; 5. Triac is the treatment of choice in patient with the resistance to thyroid hormone (RTH) syndrome. Patient with RTH have high serum TSH and thyroid hormone levels, which shows strong similarities to the profile found in AHDS patients; the longstanding experience with Triac in RTH indicates its safety and tolerability . Thus, Triac treatment could result in normalization of the abnormal serum TH values in AHDS patients. Furthermore, Triac could replace the function of T3 in tissues that depend on MCT8 for TH uptake (e.g. brain). The current trial will investigate if Triac treatment in ADHS patients 1. reduces the toxic effects of the high T3 levels 2. restores the local TH deficiency in brain.
Who is eligible to participate?
Inclusion Criteria: - clinically relevant mutation in the MCT8 gene, resulting in the clinical phenotype of AHDS. Exclusion Criteria: - Major illness or recent major surgery (within 4 weeks) unrelated to AHDS - Patients who are participating in ongoing RCTs of therapeutic interventions (including clinical trials of investigational medicinal products); - Known allergy to components in Triac tablets; - Patients that have any contra-indication for Triac treatment.
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:TriacTriac is a naturally occuring T3 metabolite with similar bioactivity and receptor binding profile.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
AHDS patientsall AHDS recruited for this study will be located in the experimental arm and will receive the investigational medicinal product Triac. The Triac dose will be individually titrated to the optimal dose level.
Active, not recruiting
Start Date: October 2014
Completed Date: May 2018
Phase: Phase 2
Primary Outcome: serum thyroid function tests
Secondary Outcome: Motor function, using the Gross Motor Function Measure
Study sponsors, principal investigator, and references
Principal Investigator: W.E. Visser, dr,
Lead Sponsor: Erasmus Medical Center
Collaborator: ZonMw: The Netherlands Organisation for Health Research and Development